Malaria is a devastating global health problem that will become much worse if resistance to frontline antimalarial drugs continues to spread. The loss of effective drug treatment of Plasmodium falciparum, especially the loss of artemisinin (ART) combination therapy (ACT), would be a global public health catastrophe. Recently, polymorphism in a regulatory protein, the Kelch K13-propeller protein was implicated in the loss of efficacy of ART drugs, but the mechanism of resistance is not understood. Understanding the mechanism of ART drug resistance (ART-R) is important for devising ACTs that inhibit further spread of ART-R and for identifying other molecular markers for surveillance and containment programs. Unfortunately, lack of experimentally validated functional information about most P. falciparum genes remains a strategic hurdle for better understanding ART-R and for development of new anti-malarial therapeutics. Better knowledge of essential metabolic pathways and vulnerabilities in the parasite's physiologic engine are critical for defining mechanisms of action of existing drugs, how resistance develops to these drugs as well molecular strategies for effective combination therapies. We propose to use a chemogenomic systems approach to define critical pathways linked to ART-R, understand mechanisms of action of ART and other antimalarial partner drugs, and predict drug combination therapies with optimal synergistic anti-parasite activity to minimize the emergence of resistance.